Summary: HIV-1 Neurotoxicity: Mechanism & Modulation by Cannabinoids Almost half of HIV-infected individuals experience HIV-associated neurocognitive disorder (HAND) which manifests as a deterioration of cognitive function; currently, there is no treatment. Our long-term goal is to inform clinical care of HAND patients by identifying novel neurophysiological changes that underlie HIV- associated cognitive decline, thereby identifying targets for therapeutic intervention. In the previous funding period we found that HIV proteins and inflammatory cytokines, factors released by HIV-infected cells, altered synaptic networks, revealing novel targets for drug development. This new proposal is oriented around preliminary data describing novel changes in the endocannabinoid (eCB) system during exposure to the HIV protein Tat. Exposure to Tat impaired eCB-mediated suppression of neurotransmitter release at excitatory but not inhibitory synapses. The eCB system suppresses aberrant synaptic activity thus, degradation of this neuroprotective system may exacerbate the synapse loss that correlates with cognitive decline in HAND. The goal of this proposal is to determine the mechanisms driving changes in eCB signaling during HIV neurotoxicity and to evaluate the consequences of these changes on network and cognitive function. In Aim 1 we will determine the mechanism of HIV Tat-induced impairment of the eCB system. We hypothesize that HIV Tat evokes release of inflammatory cytokines from glia to activate neuronal signaling pathways that impair cannabinoid type 1 receptor (CB1R)-mediated presynaptic inhibition. Pharmacological and molecular approaches will be used to determine the contribution of inflammatory cytokines and their downstream signaling pathways to impaired CB1R function. These studies will provide insight into the cellular actions of the HIV neurotoxin Tat and have broad implications for the effects of neuroinflammation on the eCB system. In Aim 2 we will determine how unbalanced eCB signaling affects network activity and cognitive function during exposure to HIV Tat. We hypothesize that exposure to HIV Tat downregulates CB1R-mediated presynaptic inhibition at excitatory synapses, thereby increasing vulnerability to excitotoxic synaptic activity. Our hypothesis predicts that in transgenic mice expressing Tat eCB signaling will be impaired in synaptic recordings from brain slices, and the loss of eCB signaling will increase the frequency of epileptiform activity detected in EEG recordings. The contribution of this aberrant activity to Tat-induced cognitive decline will be determined. These studies will relate changes in eCB signaling to network excitability in a model of HAND and link the aberrant synaptic activity induced by Tat to cognitive decline. Completion of these studies will identify a pathway induced by HIV Tat that unbalances eCB signaling. These studies will provide a foundation to explore the clinical potential of drugs that normalize excitability to improve cognitive function in HAND. Finally, the changes in eCB signaling that occur under neuroinflammatory conditions could significantly alter the effects of exogenous cannabinoids on CNS function.